Journal Article

Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1

Sambol, E B, Ambrosini, G, Carvajal, D, Schwartz, G K, Singer, S, Vassilev, L T

2007

Overview

MDM2 is a critical negative regulator of the p53 tumor suppressor protein. Recently, small-molecule antagonists of MDM2, the Nutlins, have been developed to inhibit the p53-MDM2 interaction and activate p53 signaling. However, half of human cancers have mutated p53 and they are resistant to Nutlin treatment. Here, we report that treatment of the p53-mutant malignant peripheral nerve sheath (MPNST) and p53-null HCT116 cells with cisplatin (Cis) and Nutlin-3a induced a degree of apoptosis that was significantly greater than either drug alone. Nutlin-3a also increased the cytotoxicity of both carboplatin and doxorubicin in a series of p53-mutant human tumor cell lines. In the human dedifferentiated liposarcoma cell line (LS141) and the p53 wild-type HCT116 cells, Nutlin-3a induced downregulation of E2F1 and this effect appeared to be proteasome dependent. In contrast, in MPNST and HCTp53−/− cells, Nutlin-3a inhibited the binding of E2F1 to MDM2 and induced transcriptional activation of free E2F1 in the presence of Cis-induced DNA damage. Downregulation of E2F1 by small interfering RNA significantly decreased the level of apoptosis induced by Cis and Nutlin-3a treatment. Moreover, expression of a dominant-negative form of E2F1 rescued cells from apoptosis, whereas cells overexpressing wild-type E2F1 showed an increase in cell death. This correlated with the induction of the proapoptotic proteins p73 α and Noxa, which are both regulated by E2F1. These results indicate that antagonism of MDM2 by Nutlin-3a in cells with mutant p53 enhances chemosensitivity in an E2F1-dependent manner. Nutlin-3a therefore may provide a therapeutic benefit in tumors with mutant p53 provided it is combined with chemotherapy.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Ageing, cell death / Animals / Antagonism / Antagonists / Antineoplastic Agents - pharmacology / Apoptosis / Apoptosis - drug effects / Apoptosis - genetics / Biological and medical sciences / Cancer / Carboplatin / Carboplatin - pharmacology / Cell Biology / Cell death / Cell physiology / Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes / Cellular biology / Chemical properties / Chemotherapy / Cisplatin / Cisplatin - pharmacology / Cytotoxicity / DNA damage / DNA-Binding Proteins - drug effects / DNA-Binding Proteins - metabolism / Doxorubicin / Doxorubicin - pharmacology / Drug therapy / E2F1 Transcription Factor - genetics / E2F1 Transcription Factor - metabolism / Enzyme inhibitors / Fundamental and applied biological sciences. Psychology / Genetic aspects / Genetics / Health aspects / Human Genetics / Humans / Imidazoles - metabolism / Imidazoles - pharmacology / Internal Medicine / Leukemia / Liposarcoma / MDM2 protein / Medicine / Medicine & Public Health / Mice / Molecular and cellular biology / Mutants / Nuclear Proteins - drug effects / Nuclear Proteins - metabolism / Oncology / original-article / p53 Protein / Peripheral nerves / Piperazines - metabolism / Piperazines - pharmacology / Proteasomes / Proteins / Proto-Oncogene Proteins c-bcl-2 - drug effects / Proto-Oncogene Proteins c-bcl-2 - metabolism / Proto-Oncogene Proteins c-mdm2 - metabolism / Rodents / siRNA / Transcription activation / Transcription, Genetic / Tumor cell lines / Tumor Cells, Cultured / Tumor Protein p73 / Tumor suppressor genes / Tumor Suppressor Protein p53 - drug effects / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - metabolism / Tumor Suppressor Proteins - drug effects / Tumor Suppressor Proteins - metabolism / Tumors